Outcome leads authors to recommend further studies of inflammation and neurodevelopment

A team of UC Davis researchers has found that mothers who had a fever during pregnancy were more than twice as likely to have a child with autism or developmental delay than mothers who did not have a fever or who took medication to counter its effect.

"Our study provides strong evidence that controlling fevers while pregnant may be effective in modifying the risk of having a child with autism or developmental delay," said Ousseny Zerbo, lead author of the study, who was a Ph.D. candidate with UC Davis when the study was conducted and is now a postdoctoral researcher with the Kaiser Permanente Northern California Division of Research. "We recommend that pregnant women who develop fever take anti-pyretic medications and seek medical attention if their fever persists."

Ousseny Zerbo

Published online in the Journal of Autism and Developmental Disorders, the study is believed to be the first to consider how fever from any cause, including the flu, and its treatment during pregnancy could affect the likelihood of having a child with autism or developmental delay.

The results are based on data from a large, case-control investigation known as the Childhood Autism Risk from Genetics and the Environment (CHARGE) Study led by the UC Davis MIND Institute. Another recent study based on CHARGE data found that mothers who were obese or diabetic had a higher likelihood of having children with autism.

Irva Hertz-Picciotto, a professor of public health sciences at UC Davis and principal investigator of CHARGE, pointed out that fever is produced by acute inflammation -- the short-term, natural immune system reaction to infection or injury -- and that chronic inflammation, which no longer serves a beneficial purpose and can damage healthy tissue, may be present in mothers with metabolic abnormalities like diabetes and obesity.

"Since an inflammatory state in the body accompanies obesity and diabetes as well as fever," said Hertz-Picciotto, "the natural question is: Could inflammatory factors play a role in autism?"

She explained that when people are infected by bacteria or viruses, the body generally reacts by mounting a healing response that involves the release of pro-inflammatory cytokines from white blood cells into the bloodstream. Some cytokines are able to cross the placenta, and therefore could reach the fetal central nervous system, potentially altering levels of neurotransmitters and brain development.

"We definitely think more research is necessary to pinpoint the ways that inflammation could alter brain development," said Hertz-Picciotto.

CHARGE includes an ethnically diverse population of children aged 2 to 5 years born in California and living in Northern California. The current study included 538 children with autism, 163 children with developmental delay but not autism, and 421 typically developing children whose mothers answered standardized questionnaires about whether they had the flu and/or fever during pregnancy and if they took medications to treat their illnesses.

Irva Hertz-Picciotto

The results showed that flu during pregnancy was not associated with greater risks of having a child with autism or developmental delay. Fever from any cause during pregnancy, however, was far more likely to be reported by mothers of children with autism (2.12 times higher odds) or developmental delay (2.5 times higher odds), as compared with mothers of children who were developing typically. For children of mothers who took anti-fever medication, the risk of autism was not different from the risk in children whose mothers reported no fever.

According to Irva Hertz-Picciotto, results based on CHARGE data are noteworthy because of the study's large population-based sample and detailed information on participants. Other CHARGE evaluations have found that taking prenatal vitamins prior to and during the first month of pregnancy may help prevent autism and that living near a freeway or in areas with high regional air pollution is associated with higher risk of autism in children.

"CHARGE has obtained a wealth of environmental, demographic and medical information on young children and their parents and provides a solid basis for a variety of epidemiologic studies," said Hertz-Picciotto. "Those studies are helping us find ways to protect childhood neurodevelopment."

The study, "Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (Childhood Autism Risks from Genetics and Environment) Study," was funded by the National Institute of Environmental Health Sciences (grants R01-ES015359 and P01-ES11269), the U.S. Environmental Protection Agency's STAR program (grants R-829388 and R-833292) and the UC Davis MIND Institute. The study is available at www.springerlink.com/content/x7602q07w228t313/?MUD=MP.

In addition to Zerbo and Hertz-Picciotto, other UC Davis authors were Robin Hansen of the Department of Pediatrics, Sally Ozonoff of the Department of Psychiatry and Behavioral Sciences, Cheryl Walker of the Department of Obstetrics and Gynecology and Ana-Maria Iosif of the Department of Public Health Sciences. Hertz-Picciotto, Hansen, Ozonoff and Walker are also affiliated with the UC Davis MIND (Medical Investigation of Neurodevelopmental Disorders) Institute.

Based in Sacramento, Calif., the UC Davis MIND Institute is a collaborative international research center committed to the awareness, understanding, prevention, care and cure of neurodevelopmental disorders. Utilizing the advanced biomedical technology and research infrastructure of UC Davis, the institute's scientists and clinicians pursue investigations that will ensure better futures for the one in twenty Americans with neurodevelopmental disorders.